(BQ) Part 1 book Liver pathology An atlas and concise guide presentation of content: Approach to liver specimens, normal, minor, and structural alterations, acute liver diseases, chronic liver disorders.
This page intentionally left blank LIVER PATHOLOGY An Atlas and Concise Guide This page intentionally left blank LIVER PATHOLOGY An Atlas and Concise Guide Arief A Suriawinata, MD Associate Professor of Pathology, Dartmouth Medical School Hanover, New Hampshire Department of Pathology, Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Swan N Thung, MD Professor of Pathology, and Gene & Cell Medicine The Lillian and Henry M Stratton–Hans Popper Department of Pathology The Mount Sinai School of Medicine New York, New York New York Acquisitions Editor: Richard Winters Cover Design: Joe Tenerelli Compositor: Manila Typesetting Company Printer: SCI ISBN: 978-1-933864-94-5 eISBN: 978-1-935281-48-1 Visit our website at www.demosmedpub.com © 2011 Demos Medical Publishing, LLC All rights reserved This book is protected by copyright No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher Medicine is an ever-changing science Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book Such examination is particularly important with drugs that are either rarely used or have been newly released on the market Library of Congress Cataloging-in-Publication Data Suriawinata, Arief A Liver pathology: an atlas and concise guide / Arief A Suriawinata, Swan N Thung p ; cm Includes bibliographical references and index ISBN 978-1-933864-94-5 Liver–Diseases–Atlases I Thung, Swan N II Title [DNLM: Liver Diseases–pathology–Atlases Liver–pathology–Atlases WI 17] RC846.9.S87 2011 616.3’6–dc22 2011004289 CIP data is available from the Library of Congress Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups For details, please contact: Special Sales Department Demos Medical Publishing 11 W 42nd Street, 15th Floor New York, NY 10036 Phone: 800–532–8663 or 212–683–0072 Fax: 212–941–7842 E-mail: rsantana@demosmedpub.com Made in the United States of America 11 12 13 14 15 To my parents, Bing and Gien, my wife, Jenny, and our sons, Michael and Matthew, for their enduring support and encouragement ARIEF A SURIAWINATA, MD To Roy, Stephen, Arlyne, Rohan, Anduin, Andrew, Lisa and Maile Thung; and my sisters Regina, Indah, Peni and Dewi for their continuous and loving support SWAN N THUNG, MD This page intentionally left blank Contents Foreword Preface Acknowledgments ix xi xi Approach to Liver Specimens, Normal, Minor, and Structural Alterations 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 14 16 19 21 24 27 Acute Liver Diseases 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 Approach to Liver Specimens Routine and Special Stains Immunohistochemisty Molecular Studies and Electron Microscopy Normal Liver Hepatocyte Degeneration, Death, and Regeneration Nonspecific Reactive Hepatitis, Mild Acute Hepatitis, and Residual Hepatitis Portal and Vascular Problems Brown Pigments in the Liver Acute Hepatitis Acute Hepatotropic Viral Hepatitis Acute Nonhepatotropic Viral Hepatitis Acute Hepatitis With Massive Hepatic Necrosis Granulomatous Inflammation Acute Cholestasis Alcoholic Hepatitis Drug-Induced Liver Injury Bacterial, Fungal, and Parasitic Infection Sepsis Large Bile Duct Obstruction Liver Disease in Pregnancy 31 32 35 38 41 44 47 50 53 59 64 67 70 Chronic Liver Disorders 73 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.15 74 77 81 84 87 90 93 96 99 101 105 109 114 117 120 Chronic Hepatitis Chronic Viral Hepatitis Grading and Staging of Chronic Viral Hepatitis Nonalcoholic Fatty Liver Disease Alcoholic Liver Disease Autoimmune Hepatitis Primary Biliary Cirrhosis Primary Sclerosing Cholangitis Overlap Syndromes Chronic Drug-Induced Injury Hereditary Metabolic Diseases Diagnosis of Cirrhosis Fibropolycystic Disease of the Liver Outflow Problem Intracytoplasmic Inclusions vii viii • Transplant Liver Disorders 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 Donor Liver Evaluation Preservation Injury Vascular and Biliary Tract Complications Acute Rejection Chronic Rejection Acute Hepatitis Recurrent Diseases Immune-Mediated Hepatitis and Other Findings in Late Posttransplant Biopsies Opportunistic Infections Posttransplant Lymphoproliferative Disorder Bone Marrow Transplantation Focal Lesions and Neoplastic Diseases 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 Contents Hepatic Granulomas Ductular Proliferative Lesions Cysts of the Liver Hepatic Abscess, Inflammatory Pseudotumor, and Hydatid Cysts Benign Hepatocellular Tumors Nodules in Cirrhosis Hepatocellular Carcinoma Cholangiocarcinoma Vascular Lesions Lipomatous Lesions Other Mesenchymal Tumors Lymphoma and Leukemia Metastatic Tumors Tumor-Associated Changes Pediatric Liver Diseases 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Pediatric Liver Biopsy Neonatal Hepatitis Syndrome Extrahepatic Biliary Atresia and Paucity of Intrahepatic Bile Duct Fatty Liver Disease Total Parenteral Nutrition–Induced Cholestatic Liver Disease Congenital Hepatic Fibrosis Progressive Familial Intrahepatic Cholestasis Hereditary and Metabolic Liver Disorder Pediatric Liver Tumors Suggested Readings Index 125 126 129 132 135 138 141 143 147 149 151 154 157 158 162 165 168 171 177 181 187 192 196 199 201 205 209 211 212 215 218 222 225 228 231 234 238 243 255 110 • Chronic Liver Disorders Figure 3.12.1 Cirrhosis with different sizes of regenerative nodules Figure 3.12.2 Fragmentation of biopsy specimen in cirrhosis (trichrome stain) Figure 3.12.3 Cirrhosis secondary to steatohepatitis with steatotic regenerative nodules and hypocellular fibrous septa Figure 3.12.4 Alcoholic micronodular cirrhosis Figure 3.12.5 Cirrhosis showing regenerative nodules with variation of regenerative activity of hepatocytes and concentric hepatocyte plates (arrowheads) Figure 3.12.6 Concentric arrangement of hepatocyte plates and “differential regeneration” of hepatocytes suggestive of cirrhosis 3.12 Diagnosis of Cirrhosis • 111 Figure 3.12.7 Connective tissue rim over more than half of circumference of nodule in cirrhosis (trichrome stain) Figure 3.12.8 Hepatitis C cirrhosis with dense lymphocytic infiltrate in portal tracts Figure 3.12.9 Mosaic or “jigsaw puzzle” pattern in biliary cirrhosis Figure 3.12.10 Regressed fibrosis in patient successfully treated for chronic hepatitis B, showing delicate fibrous septa and absence of inflammation Figure 3.12.11 Regressed fibrosis with thin mature fibrous septa, irregular arrangement of portal tract and hepatic veins, and absence of interface hepatitis and lobular necroinflammatory activity Figure 3.12.12 Postnecrotic cirrhosis after acetaminophen toxicity The parenchymal nodules are separated by broad fibrous bands 112 • Chronic Liver Disorders Table 3.12.1 Diagnosis of Cirrhosis Definite Features of Cirrhosis Suggestive Features of Cirrhosis Suggestive Features of Incomplete Cirrhosis/Regressed Fibrosis Parenchymal nodules surrounded entirely by fibrous tissue Fragmentation of a needle biopsy specimen into round parenchymal pieces Fragmentation of a needle biopsy specimen into expansive sheets of liver parenchyma without portal tracts and without obvious central hepatic venules Fibrous septa linking portal tracts and central venules Septa between portal tracts or between central venules in advanced fibrosis Connective tissue rim over more than half of the circumference of a parenchymal fragment Delicate remnants of mature fibrous septa Fibrous septa extending from portal tracts into parenchyma without reaching the central venules Irregular arrangement of portal tracts and hepatic veins Concentric arrangement of hepatocyte plates, particularly at the periphery of parenchymal fragments Irregularity of parenchymal atrophy and hyperplasia (nodular regeneration) Variations in the degree of regenerative activity of hepatocytes resulting in differences in nuclear and cell size, plate thickness (“differential regeneration”) and compression of adjacent liver tissue Regenerative activity of hepatocytes resulting in differences in plate thickness Variations between nodules in the content of fat, glycogen iron, lipofuscin, copper, bile or inflammatory cells Absence of interface hepatitis or lobular necroinflammatory activity Disproportion between portal tracts and central venules with reduction in number, absence or hypoplasia of portal tracts and increased number of hepatic veins Absence of fat or ballooning degeneration of hepatocytes 3.12 Table 3.12.2 Diagnosis of Cirrhosis • 113 Conditions Mimicking Cirrhosis Diagnosis Histologic Features Alcoholic central hyalin sclerosis Severe extinction of centrilobular hepatocytes replaced by fibrosis, chicken-wire fibrosis, Mallory-Denk bodies, neutrophils No regenerative nodules, portal tracts initially normal Long standing severe congestive heart failure Centrilobular dilatation of sinusoids and central venules, followed by perisinusoidal fibrosis, hepatocyte atrophy containing small droplet fat or lipofuscin pigment No regenerative nodules Secondary biliary cirrhosis from prolonged bile duct obstruction Portal and perilobular fibrosis, dilated bile ducts with periductal fibrosis, cholate-stasis in periportal hepatocytes No regenerative nodules Hepatic schistosomiasis Fibrous obliteration and thickening portal vein branches, extensive dense portal fibrosis (so-so called pipestem fibrosis), thin-walled vascular channels in portal tracts and septa Granuloma with schistosoma eggs, hemozoin pigment in Kupffer cells and portal tracts Hypervitaminosis A Extensive fibrosis along sinusoids Hepatic stellate cell hyperplasia containing fat globules and scalloping of the nuclei Myeloproliferative disorders Extramedullary hematopoiesis accompanied by fibrosis of the sinusoids Congenital hepatic fibrosis Dense fibrous septa separating islands of normal liver parenchyma Elongated or cystic well-formed bile duct structures in the periphery of portal tracts or scattered throughout fibrous septa Veno-occlusive disease Congestion of centrilobular and midzonal region with occlusion of central venules by loose fibrous tissue Nodular regenerative hyperplasia Hyperplastic parenchymal nodule without fibrous septa, compression of surrounding parenchyma with congestion Hepatoportal sclerosis Portal fibrosis, thickening, absence or marked narrowing of portal veins, localized engorgement of periportal sinusoids, parenchymal atrophy accompanied by sinusoidal dilatation Portal vein thrombosis Portal vein fibrosis or obliteration, centrilobular hepatocyte atrophy with sinusoidal dilatation, reverse lobulation Gaucher disease Accumulation of pale macrophages in portal tracts and sinusoids with striated cytoplasmic appearance Sarcoidosis Multiple often coalescing nonnecrotizing epithelioid granulomas with associated fibrosis 3.13 Fibropolycystic Disease of the Liver Fibropolycystic disease of the liver is a group of congenital diseases caused by embryonal ductal plate malformation that includes congenital hepatic fibrosis, polycystic liver disease, Caroli disease, and biliary microhamartoma (von Meyenburg complex) The defect “cholangiociliopathy” allows the possibility that different diseases are expressed alone or in various combinations in the same liver In addition, different family members of a proband may exhibit different abnormalities of the biliary tree Fibropolycystic diseases clinically result in effects depending on which abnormality predominates: spaceoccupying lesions (polycystic liver disease), portal hypertension (congenital hepatic fibrosis), and cholangitis (Caroli disease) Biliary microhamartomas not give rise to liver abnormalities or symptoms but may be seen in association with other forms of fibropolycystic disease Cholangiography and other imaging methods of liver and bile ducts and liver biopsy are important for the diagnosis Polycystic disease of the kidneys is associated to a variable extent Cholangiocarcinoma may complicate this disease Caroli Disease Caroli disease may affect different parts of the intrahepatic biliary tree and is seen alone or in combination with other forms of fibropolycystic liver disease, particularly congenital hepatic fibrosis (Caroli syndrome) It is characterized by segmental saccular dilatations of the intrahepatic bile ducts, surrounded by extensive fibrosis (Figure 3.13.3) The dilated ducts connect with the main duct system Therefore, bile duct cysts in Caroli disease often contain inspissated bile or bile stones and show chronic inflammatory infiltrate and neutrophilic infiltrate from recurrent ascending cholangitis or abscess formation (Figure 3.13.4) Acute inflammation is often superimposed with ulceration of the bile duct epithelium and pus in the lumen mixed with bile and mucus When the epithelium of the cystic bile ducts is preserved, it is often columnar and hypertrophic Antibiotic treatment may be required for cholangitis Recurrent drainage of the bile ducts may be required to remove calculi Localized involvement may be treated by resection Liver transplantation may be an option in diffuse disease Congenital Hepatic Fibrosis Polycystic Liver Disease Congenital hepatic fibrosis occurs both in sporadic form and familial form with autosomal recessive inheritance It is often associated with autosomal recessive polycystic kidney disease, which may manifest in early life, whereas the liver disease is diagnosed between ages and 10 years or even later In congenital hepatic fibrosis, islands of normal liver parenchyma are separated by broad or narrow septa of dense mature fibrous tissue containing elongated or cystic well-formed bile duct structures, sometimes filled with inspissated bile (Figures 3.13.1 and 3.13.2) Portal tracts are incorporated in the fibrous bands and may contain normal or ectatic interlobular bile ducts in the center Portal vein branches are hypoplastic or completely absent The parenchymal islands vary in shape like mosaic and maintain a normal vascular relationship with central venules The hepatocytes are arranged in regular plates rather than regenerative 2-cell-thick plates forming true nodules as in cirrhosis There is no inflammation in the parenchyma or in the fibrous septa Inflammation, cholestasis, and/or cholangitis should raise the possibility of associated Caroli disease or choledochal cyst Congenital hepatic fibrosis must be distinguished from cirrhosis Because liver function is preserved in congenital hepatic fibrosis, the prognosis is considerably better following portacaval shunt to relieve portal hypertension Polycystic liver disease causes nodular enlargement of the liver, but hepatic function is normal It may involve the liver diffusely or restricted to one lobe, usually the left lobe The cysts measure up to 10 cm in diameter filled with clear or rarely hemorrhagic fluid The cysts in polycystic liver disease are not connected with the main biliary system The cysts are lined by low cuboidal or flattened biliary epithelial cells (Figure 3.13.5) They not contain bile, and there is no associated cholangitis Frequently, microhamartomas are also present Polycystic liver disease is compatible with long life The prognosis depends on the associated polycystic renal disease Aspiration of the cysts or surgical resection may be considered for large cysts 114 Biliary Microhamartomas Biliary microhamartomas are common in patients with congenital hepatic fibrosis and polycystic liver disease Biliary microhamartomas (von Meyenburg complexes) are located in or close to portal tracts and rarely exceed mm in diameter They represent solitary or multiple small nodules of dense collagen containing many interconnecting mature bile duct structures lined by cuboidal biliary epithelium, which often contain inspissated bile (Figure 3.13.6) Biliary microhamartomas not require treatment 3.13 Fibropolycystic Disease of the Liver • 115 Figure 3.13.1 Broad and thin mature fibrous septa containing elongated and dilated interconnecting bile duct structure, separating islands of normal liver parenchyma, in congenital hepatic fibrosis Figure 3.13.2 Congenital hepatic fibrosis with interconnecting dilated bile duct structure in mature fibrous septa Figure 3.13.3 Figure 3.13.4 Cystic bile duct in Caroli disease with acute cholangitis Cystic bile duct in Caroli disease Figure 3.13.5 Multiple cysts lined by flat to cuboidal biliary epithelium in polycystic liver disease Figure 3.13.6 Biliary microhamartoma (Meyenburg complex) composed of small bile duct structures lined by cuboidal biliary epithelium containing inspissated bile 116 • Chronic Liver Disorders Table 3.13.1 Fibropolycystic Disease of the Liver Characteristics Congenital Hepatic Fibrosis Caroli Disease Polycystic Liver Disease Biliary Microhamartoma Genetic mutation Fibrocystin gene Not identified Polycystin-1 and polycystin-2 genes (PKD1, PKD2) Not identified Age, sex 3-10 years old, rarely later age Any age, M>F Adult, F>M Clinical features Portal hypertension, splenomegaly, large firm liver Recurrent fever, jaundice, abdominal pain, hepatomegaly Abdominal pain, hepatomegaly Asymptomatic Inheritance Sporadic, autosomal recessive Autosomal recessive or dominant Autosomal dominant Sporadic, autosomal recessive or dominant Association Autosomal recessive polycystic kidney disease, Caroli disease Congenital hepatic fibrosis Autosomal dominant polycystic kidney disease Congenital hepatic fibrosis, polycystic liver disease Liver enzyme activities Normal Cholestatic Normal Normal Communication with biliary tree No Yes No No Cyst features Persistent cystic Dilated segmental bile duct plate remnants ducts, often wrapping in periphery of hepatic artery portal tracts Multiple large cysts, Dilated or tortuous small massively replacing ductular structures liver parenchyma embedded in hyalinized stroma, near or in portal tracts Cyst content Inspissated bile Clear fluid Bile, inflammatory cells, pus Inspissated bile 3.14 Outflow Problem Although there are different etiologies, pathogeneses, and location, anatomical or functional venous outflow obstruction results in similar clinical symptoms In severe acute stage, patients present with sudden onset of high-protein ascites, painful hepatomegaly, and mild jaundice In chronic form, patients present with an enlarged tender liver, ascites, and other signs and symptoms of portal hypertension as seen in cirrhosis Causes of venous outflow obstruction include Budd-Chiari syndrome (BCS) and veno-occlusive disease (VOD) Chronic passive congestion of the liver may become so severe that it resembles BCS or VOD Alcoholic central hyalin sclerosis produces extensive centrilobular fibrosis that may mimic outflow problem There are similarities in gross and histologic features in BCS, VOD, and severe chronic passive congestion: nutmeg liver, centrilobular sinusoidal dilatation, extravasation of red blood cells to the space of Disse, atrophy of centrilobular hepatocytes, centrilobular hemosiderin deposition in Kupffer cells, preservation and regenerative hyperplasia of periportal hepatocytes, and unremarkable portal tracts Budd-Chiari syndrome Budd-Chiari syndrome is characterized by occlusion of large hepatic veins or intrahepatic or suprahepatic portion of the inferior vena cava Budd-Chiari syndrome occurs in patients with hypercoagulable states, particularly myeloproliferative disorders, acquired and inherited thrombophilias, and oral contraceptives (primary BCS); malignant neoplasms such as renal cell carcinoma or hepatocellular carcinomas growing into the inferior vena cava; trauma; or membranous obstruction of the inferior vena cava (secondary BCS) In both BCS and VOD, the liver is dark red and enlarged with rounded edges The cut surface shows dark red areas with centrilobular congestion and congestive bridges surrounding pale brown parenchyma, which represents reverse lobulation and results in a nutmeg appearance Regenerative hyperplasia leads to yellow to pale brown nodular areas Thickened hepatic veins may be demonstrable Caudate lobe enlargement is a characteristic finding in BCS Budd-Chiari syndrome causes severe dilatation and congestion of centrilobular and midzonal sinusoids with extravasation of red blood cells into the space of Disse and hepatic plates (Figure 3.14.1) This results in compression and loss of hepatocytes with formation of blood lakes The periportal hepatocytes are relatively preserved, and the portal tracts are intact Chronic BCS leads to extensive centrilobular fibrosis with fibrous bridges to adjacent centrilobular areas (Figure 3.14.2) Hemosiderin deposition is noted in Kupffer cells in the centrilobular areas The central venules are patent and dilated Veno-occlusive disease Veno-occlusive disease is characterized by occlusion of the central hepatic venules and sublobular hepatic veins as the result of endothelial damage from, among others, pyrrolizidine alkaloids in herbal teas, radiation to the liver, or chemotherapy, particularly in association with bone marrow transplantation The gross findings in VOD are similar to those of BCS, except for the presence of occlusion that may be seen in hepatic venules or veins of VOD cases Veno-occlusive disease causes dilatation and congestion of centrilobular and midzonal sinusoids with extravasation or red blood cells into the space of Disse, similar to those seen in BCS, but in VOD, the central hepatic venules and sublobular veins show subintimal edema, fibrin deposition, and partial to complete occlusion of the lumen by loose fibrous tissue (Figures 3.14.3 and 3.14.4) Venous occlusion may be focal and difficult to find in biopsy specimens In chronic stage, fibrous tissue is deposited in centrilobular sinusoids with formation of fibrous bridges to adjacent centrilobular areas and is referred to as “sinusoidal obstruction syndrome.” Chronic Passive Congestion Chronic passive congestion is seen in patients with congestive heart failure due to coronary artery disease, cardiomyopathy, valvular diseases, and constrictive pericarditis It may lead to cardiac cirrhosis Patients with chronic passive congestion present with mild jaundice, right upper abdominal pain, enlarged tender liver, and ascites similar to the other disorders, but features of portal hypertension are usually absent, except for splenomegaly Cardiac problems are usually the major manifestations Chronic passive congestion is characterized by dilatation and congestion of central venules and centrilobular sinusoids with compression of the hepatocytes (Figure 3.14.5) The latter contain increased amount of lipofuscin, fat globules, and sometimes bile pigments in the cytoplasm or bile plugs in canaliculi In severe, long-standing cases, centrilobular hepatocytes are replaced by fibrous tissue The central venules, however, remain patent, although the wall may be thickened and the surrounding sinusoids are engorged All of this results in reversed lobulation with normal portal tracts surrounded by unaffected parenchyma (Figure 3.14.6) Eventually, fibrous bridges form between adjacent centrilobular areas, but regenerative nodules and true cirrhosis are extremely rare In some patients, intracytoplasmic PAS-positive globules can be seen in a centrilobular congested area, morphologically similar to those of α-1-antitrypsin globules but in centrilobular and not in periportal location (see “Intracytoplasmic Inclusions”) 117 118 • Chronic Liver Disorders Figure 3.14.1 Centrilobular necrosis in Budd-Chiari syndrome (arrows) with midzonal sinusoidal dilatation Figure 3.14.2 Chronic Budd-Chiari syndrome with centrilobular fibrosis, congestion, hepatocyte atrophy, and hemosiderin in Kupffer cells Figure 3.14.3 Occluded central venule (arrow) in venoocclusive disease (trichrome stain) Figure 3.14.4 Occluded central venule (arrow) and sinusoidal fibrosis in radiation-induced veno-occlusive disease Figure 3.14.5 Chronic passive congestion with dilated and thickened central venule, centrilobular sinusoidal dilatation, small droplet fat in centrilobular hepatocytes, and extravasation of red blood cells to the space of Disse (arrow) Figure 3.14.6 “Cardiac sclerosis” with centrilobular sinusoidal dilatation, fibrosis, and reverse lobulation of parenchyma 3.14 Table 3.14.1 Outflow Problem • 119 Differential Diagnosis of Outflow Problem Histologic Features Chronic Passive Congestion Budd-Chiari Syndrome Veno-Occlusive Disease Alcoholic Central Hyalin Sclerosis Centrilobular congestion + ++ + – Extravasation of red blood cells + (when severe)/– ++ + – Central venule dilatation + + – – Central venule thickening ++ ++ + ++ Central venule occlusion – +/– + ++ Sinusoidal dilatation ++ + + – Centrilobular steatosis + – – ++ Reverse lobulation + + + – Centrilobular hemosiderosis + ++ ++ – Mallory-Denk bodies – – – ++ ++ indicates almost always present; +, usually present; +/–, occasionally present; –, usually absent 3.15 Intracytoplasmic Inclusions There are common morphologic categories of intracytoplasmic inclusions associated with various chronic liver diseases, metabolic liver diseases, and drug-induced liver injury: (1) globular eosinophilic inclusions, (2) coarse eosinophilic inclusions, and (3) ground glass–like inclusions In addition, many of these inclusions are often exaggerated in hepatocellular carcinoma, necessitating the differential diagnosis of hepatocellular carcinoma when inclusions are present in abundance and a neoplasm is suspected Globular Eosinophilic Inclusions Inclusions in this category are characterized by single or multiple, round to oval eosinophilic intracytoplasmic globules, including α-1-antitrypsin (AAT) inclusions, passive congestion inclusions, and giant mitochondria α-1-antitrypsin inclusions are predominantly periportal or periseptal in location (Figure 3.15.1) The globules are larger, multiple, and more easily identified on hematoxylin-eosin in older individuals or cirrhotic liver due to AAT deficiency Immunohistochemical stain for AAT is confirmatory and more sensitive than PAS-D stain (Figures 3.15.2 and 3.11.12) Passive congestion inclusions demonstrate similar characteristics and positivity for PAS and PAS-D stains as AAT, but passive congestion inclusions are predominantly located in the congested centrilobular region and often concurrent with fat vacuoles as the result of hypoxia (Figures 3.15.4 and 3.15.5) Passive congestion inclusions tend to be more regular in size when compared with AAT inclusions Giant mitochondria or megamitochondria are round to spindle-shaped inclusions, often present in alcoholic liver disease and to a lesser extent in NASH In alcoholic liver disease, they are predominantly distributed in a centrilobular area and associated with hepatocyte ballooning In NASH, they can be seen in the periportal area They are similar in color to AAT inclusions on H&E–stained slides but usually no more than to giant mitochondria per hepatocytes (Figure 3.15.3) Irregularly Shaped Eosinophilic Inclusions Mallory-Denk hyalins are the only irregularly shaped eosinophilic inclusions identified in hepatocytes (Figure 3.15.6) They represent clumps or strands of intermediate filaments of the cytoskeleton, which are positive for cytokeratins and 18, ubiquitin, and p62 Mallory-Denk hyalins are the hallmark of ASH and NASH They are also seen in a variety of other chronic liver disorders with chronic cholestasis and/or cholate stasis, particularly late stages of PBC and PSC; in Wilson 120 disease; in drug-induced liver diseases; and in hepatocellular carcinoma Ground Glass–Like Inclusions Inclusions in this category include HBsAg inclusions, fibrinogen inclusions, Lafora bodies, and Lafora-like bodies or polyglucosan inclusions They are characterized by finely granular, pale eosinophilic ground glass–like appearance, often surrounded by a “halo” and when large becomes crescentic and displaces hepatocyte nucleus to the periphery Other eosinophilic changes that can be confused with ground glass hepatocytes are hepatic oncocytes and induction cells Hepatitis B surface antigen accumulates in the smooth endoplasmic reticulum producing the classic pale, finely granular “ground glass hepatocytes,” encountered in patients with chronic hepatitis B, and their presence can be detected by immunohistochemical stain for HBsAg and orcein or Victoria blue stain (Figure 3.15.7) Fibrinogen inclusion varies from round deeply eosinophilic inclusion to finely granular pale eosinophilic inclusion, seen in fibrinogen storage diseases (Figure 3.15.10) In hepatocellular carcinoma and fibrolamellar carcinoma, fibrinogen inclusions are referred as “pale bodies.” Lafora bodies in hepatocytes are seen in patients with progressive familial myoclonic epilepsy (Figure 3.15.8) They are identified by their content of mucopolysaccharides Lafora-like bodies or polyglucosan inclusions fundamentally are non–membrane-bound intracytoplasmic glycogen that can be encountered in various liver diseases, such as glycogenosis type IV, cyanamide aversion therapy for alcohol abuse, and polyglucosan body disease (Figure 3.15.9) The term pseudo–ground glass for these inclusions was previously used in patients with polypharmacotherapy Induction bodies are pale ground-glass–like cytoplasmic inclusion seen in drug-induced injury, particularly barbiturates, chlorpromazine, or azathioprine that cause induction of cytochrome P450, resulting in increase of smooth endoplasmic reticulum They are located in the periportal or centrilobular area (Figure 3.15.12) Hepatic oncocytes (also known as oncocytic hepatocytes) are hepatocytes with distinctively dense, finely granular, and strongly eosinophilic cytoplasm due to densely packed mitochondria, resembling oncocytes in other exocrine or endocrine glands (Figure 3.15.11) Hepatic oncocytes are found only in cirrhosis of various etiologies They are located primarily adjacent to the periportal or periseptal area and are often surrounded by fibrous tissue 3.15 Intracytoplasmic Inclusions • 121 Figure 3.15.1 a-1-Antitrypsin globules in a-1-antitrypsin deficiency are faintly eosinophilic, better visualized on trichrome stain (inset) or PAS-D stain Figure 3.15.2 PAS-D stain shows irregular distribution of a-1-Antitrypsin globules in cirrhotic nodules Figure 3.15.3 Giant mitochondria (arrows) are better visualized in ballooned hepatocytes in steatohepatitis Figure 3.15.4 Chronic passive congestion showing centrilobular eosinophilic globules (arrowheads) in hepatocytes in the area of congestion Figure 3.15.5 Centrilobular globules in chronic passive congestion are positive for PAS-D, similar to a-1antitrypsin globules Figure 3.15.6 Amiodarone-induced liver injury with numerous irregularly shaped Mallory-Denk hyalins MalloryDenk hyalin is red in trichrome stain (inset) 122 • Chronic Liver Disorders Figure 3.15.7 Chronic hepatitis B showing numerous ground glass hepatocytes Figure 3.15.9 Polyglucosan bodies or pseudo–ground glass hepatocytes in polypharmacotherapy Figure 3.15.11 Numerous hepatic oncocytes or oncocytic hepatocytes (arrows) in cirrhosis as the result of densely packed mitochondria may be confused with ground glass hepatocytes in chronic hepatitis B Figure 3.15.8 Lafora bodies in myoclonus epilepsy consisting of predominantly non–membrane-bound mucopolysaccharide deposition Figure 3.15.10 Fibrinogen pale eosinophilic inclusion in fibrinogen storage disease (PAS-D stain) Figure 3.15.12 Increased in smooth endoplasmic reticulum producing pale ground glass-like hepatocytes “induction cells” in drug-induced injury 3.15 Table 3.15.1 Intracytoplasmic Inclusions • 123 Intracytoplasmic Inclusions Location Trichrome PAS-D PTAH Orcein or Colloidal Ultrastructure HBsAg Iron Associated Conditions Globular eosinopilic inclusion red + – – – Finely granular a-1-Antitrypsin material in deficiency, dilated endoplascirrhosis mic reticulum or caused by other in membraneconditions bound vacuoles Giant (or mega-) Centrilobular mitochondria (alcoholic), periportal (nonalcoholic) red – + – – Dilated mitochondria with crystalloid bodies Passive congestion inclusion red/blue + – – – Microfibrillar Chronic passive material with congestion occasional rodshaped material in lysosomes Centrilobular red/purple – (steatohepatitis), periportal (chronic cholestasis) – – – Cytokeratin intermediate filament a-1-Antirypsin inclusion Periportal Centrilobular Alcoholic and nonalcoholic steatohepatitis Coarse eosinophilic inclusion Mallory-Denk hyalin Alcoholic and nonalcoholic steatohepatitis, Wilson’s disease, drug induced injury, hepatocellular carcinoma Ground glass-like inclusion Hepatitis B surface antigen inclusion Azonal light red – – + – Chronic hepatitis Hepatitis B B infection surface antigen in smooth endoplasmic reticulum Fibrinogen Azonal gray/light blue – +/– – – Dilated rough endoplasmic reticulum with tubular fingerprint-like structures Lafora(-like) bodies or polyglucosan inclusion Azonal light red – – – + PolypharmacoIntracytoplasmic therapy, polyglycogen granglucosan body ules, non memdisease, glycobrane bound genosis type IV, myoclonus epilepsy (Lafora’s disease), cyanamide aversion therapy for alcohol abuse Hepatic oncocytes Periseptal or periportal in cirrhosis red – + – – Densely packed mitochondria Induction hepatocytes Periportal or centrilobular light red/ gray – – – – Increased smooth Drug-induced endoplasmic injury reticulum Fibrinogen storage disease, hepatocellular carcinoma (pale bodies) Cirrhosis of various etiologies PAS indicates periodic acid–Schiff; PAS-D, periodic acid–Schiff with diastase digestion; PTAH, phosphotungstic acid hematoxylin; HBsAg, hepatitis B surface antigen; +, positive; –, negative; +/–, weakly positive This page intentionally left blank ... and Metabolic Liver Disorder Pediatric Liver Tumors Suggested Readings Index 12 5 12 6 12 9 13 2 13 5 13 8 14 1 14 3 14 7 14 9 15 1 15 4 15 7 15 8 16 2 16 5 16 8 17 1 17 7 18 1 18 7 19 2 19 6 19 9 2 01 205 209 211 212 ... 3 .10 3 .11 3 .12 3 .13 3 .14 3 .15 74 77 81 84 87 90 93 96 99 10 1 10 5 10 9 11 4 11 7 12 0 Chronic Hepatitis Chronic Viral Hepatitis Grading and Staging of Chronic Viral Hepatitis Nonalcoholic Fatty Liver. .. intentionally left blank LIVER PATHOLOGY An Atlas and Concise Guide This page intentionally left blank LIVER PATHOLOGY An Atlas and Concise Guide Arief A Suriawinata, MD Associate Professor of Pathology,